Department of Pathology, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, PR China; Department of Pathology, Baoji Central Hospital, Baoji, PR China.
Department of Pathology, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, PR China.
Arch Biochem Biophys. 2020 Oct 30;693:108571. doi: 10.1016/j.abb.2020.108571. Epub 2020 Sep 6.
Chemotherapy resistance is one of the major challenges for the treatment of hepatocellular carcinoma (HCC). In order to investigate the mechanisms involved in chemoresistance of HCC, we established cisplatin (CDDP) and doxorubicin (Dox) resistant HCC cells. The expression of transcriptional coactivator with PDZ-binding motif (TAZ), one of the major downstream effectors of Hippo pathway, was upregulated in chemoresistant HCC cells. Targeted inhibition of TAZ via its siRNAs can restore CDDP and Dox sensitivity of chemoresistant HCC cells. The upregulation of TAZ increased the expression of IL-8 in HCC/CDDP and HCC/Dox cells. Recombinant IL-8 (rIL-8) antagonized the increased chemosensitivity mediated by TAZ knockdown. Mechanistically, TAZ can directly bind with the promoter of IL-8 to activate its transcription in chemoresistant HCC cells. Collectively, our data showed that TAZ-regulated expression of IL-8 was involved in chemoresistance of HCC cells. It indicated that targeted inhibition of TAZ/IL-8 axis might be helpful to improve chemotherapy efficiency for HCC.
化疗耐药性是肝细胞癌 (HCC) 治疗的主要挑战之一。为了研究 HCC 化疗耐药性涉及的机制，我们建立了顺铂 (CDDP) 和阿霉素 (Dox) 耐药 HCC 细胞系。转录共激活因子与 PDZ 结合基序 (TAZ) 的表达在化疗耐药 HCC 细胞中上调，Hippo 通路的主要下游效应物之一。通过其 siRNA 靶向抑制 TAZ 可以恢复耐药 HCC 细胞对 CDDP 和 Dox 的敏感性。TAZ 的上调增加了 HCC/CDDP 和 HCC/Dox 细胞中 IL-8 的表达。重组白细胞介素-8(rIL-8) 拮抗了 TAZ 敲低介导的增加的化疗敏感性。在机制上，TAZ 可以直接与 IL-8 的启动子结合，在耐药 HCC 细胞中激活其转录。总的来说，我们的数据表明 TAZ 调节的 IL-8 表达参与了 HCC 细胞的化疗耐药性。这表明靶向抑制 TAZ/IL-8 轴可能有助于提高 HCC 的化疗效率。
